Project Summary Abstract: Influenza vaccination is the most effective means of preventing influenza virus infection and its more severe complications. Due to the changing nature of influenza viruses, active surveillance alongside regular updating of vaccine components and annual vaccination are necessary for vaccine protection. There is a need for annual evaluation of vaccine effectiveness (VE), which may vary from year to year. These estimates are critical to inform the medical community, maintain public confidence in the vaccine, and determine the effect of virus drift on protection. Modern study designs to assess VE require laboratory confirmation of influenza infection, sensitive and specific measures of vaccine receipt, and the use of a case test-negative design to control for differences in healthcare-seeking behavior between vaccinated and unvaccinated patients. We propose to use these methods to estimate influenza VE in preventing influenza-associated ambulatory care visits in two health systems in Michigan, where we have been conducting annual assessments of VE since 2008. We will conduct surveillance at adult and pediatric outpatient clinics, and we will enroll patients seeking care for acute respiratory infections meeting a standard case definition. Vaccination status will be reported and documented, and considered with laboratory-confirmed influenza outcomes to estimate VE in preventing influenza- associated health care visits. Analyses will use the case test-negative design; those testing positive for influenza will be cases, those testing negative will be controls. Modifiers and confounders of VE such as age, health status, high-risk health conditions, education, time from illness onset to specimen collection, and calendar time will be assessed. We will also estimate the population-based incidence of medically-attended influenza and will identify infections due to respiratory syncytial virus (RSV) and other respiratory viruses in later years of the study. We will pilot methods to monitor the development of influenza virus resistance to antiviral medications which could inform similar studies carried out in a potential future influenza pandemic. In addition to our proposed influenza surveillance and VE assessment in the outpatient setting, we propose to continue our analyses of influenza VE and development of influenza antibodies among a prospectively followed cohort of households with children which has been in place since 2010. This cohort will be used to carry out complementary analyses of VE in preventing influenza illnesses of any severity which will be identified through ongoing active surveillance. Households in this cohort are followed for multiple years, enabling precise evaluations of repeated vaccination. Our current enrollment strategies will be augmented with targeted enrollment of households with children under age 3. Blood specimens will be collected from adults and children twice yearly; a third blood specimen will be collected from children < 3 years old 4 weeks after vaccination. The proposed work will enable the continuation of our established, coordinated, multi-faceted evaluation of influenza VE and development of antibodies in both ambulatory and community settings.